The role of eIF4 in cell proliferation.

Translational control has a key role in regulating cell growth. The mRNA binding translation factors (eIF4s) selectively modulate the translation of different mRNAs based on their differing properties, especially the extent of inhibitory secondary structure in their 5' untranslated regions. The mRNA 5' cap is recognized by eIF4E, which can then recruit other translation factors including the helicase cIF4A. Overexpression of eIF4E leads to cell transformation or disordered growth. It also enhances the translation of certain mRNAs, including that for cyclin D1. Decreased expression of eIF4E leads to reduced rates of cell growth. Transformed cells express elevated levels of eIF4E. eIF4E is subject to phosphorylation, which is increased by agents that stimulate translation. However, the role of eIF4E phosphorylation and the signalling pathways through which it is controlled remain to be elucidated. Oncogenic ras leads to increased phosphorylation of eIF4E, and the ability of ras to transform cells is diminished when eIF4E expression is decreased, implying that eIF4E is a key mediator of ras mediated transformation. The recent discovery of inhibitors of eIF4E (eIF4E binding proteins, 4EBP1/2) adds another regulatory component to the system. Although a role for 4EBP1 in cell transformation (or rather in impeding it) has yet to be established, this is an exciting and likely possibility. It should also be noted that 4EBP1 seems to be under the control of the p70S6K pathway, which has a role in cell cycle progression.